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Radiation necrosis in renal cell carcinoma brain metastases treated with checkpoint inhibitors and radiosurgery: An international multicenter study

Lehrer, Eric J; Gurewitz, Jason; Bernstein, Kenneth; Patel, Dev; Kondziolka, Douglas; Niranjan, Ajay; Wei, Zhishuo; Lunsford, L Dade; Malouff, Timothy D; Ruiz-Garcia, Henry; Patel, Samir; Bonney, Phillip A; Hwang, Lindsay; Yu, Cheng; Zada, Gabriel; Mathieu, David; Trudel, Claire; Prasad, Rahul N; Palmer, Joshua D; Jones, Brianna M; Sharma, Sonam; Fakhoury, Kareem R; Rusthoven, Chad G; Deibert, Christopher P; Picozzi, Piero; Franzini, Andrea; Attuati, Luca; Lee, Cheng-Chia; Yang, Huai-Che; Ahluwalia, Manmeet S; Sheehan, Jason P; Trifiletti, Daniel M
BACKGROUND:Patients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited. METHODS:test. Univariable logistic regression was used to identify factors associated with developing RN. RESULTS:). Any-grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99-1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17-2.30; P = .76), prior WBRT, and ICI agents were not statistically significant. CONCLUSIONS:Symptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single-fraction SRS.
PMID: 35077586
ISSN: 1097-0142
CID: 5152552

Stereotactic radiosurgery for the treatment of hypoglossal schwannoma: a multi-institutional retrospective study

Dabhi, Nisha; Pikis, Stylianos; Mantziaris, Georgios; Tripathi, Manjul; Warnick, Ronald; Peker, Selcuk; Samanci, Yavuz; Berger, Assaf; Bernstein, Kenneth; Kondziolka, Douglas; Niranjan, Ajay; Lunsford, L Dade; Sheehan, Jason P
BACKGROUND:Surgical removal has been performed as the first line treatment for symptomatic or enlarging hypoglossal schwannomas (HS). Stereotactic radiosurgery (SRS) offers a minimally invasive approach that may afford long-term tumor control for patients with HS particularly those who refuse or are unfit for surgery. This study evaluates outcomes after SRS performed for both newly diagnosed and residual tumors after incomplete resection. METHODS:This retrospective, multi-institutional study involved patients treated with adjuvant or primary SRS for HS. The study end-points included local tumor response, clinical outcomes, and procedure-related complications. All the patients had Gamma Knife SRS. RESULTS:(range, 0.7-27.23). At median imaging follow-up of 37 months (range, 6-153), tumor control was achieved in 11 patients. Tumor enlargement that was managed with surgical resection was noted at the 6-month follow-up in one patient. At median clinical follow-up of 30.5 months (range, 6-157), stability, or improvement of all pre-SRS signs and symptoms was noted in nine patients. Two patients experienced worsening of at least one pre-existing symptoms or sign. New-onset trapezius weakness was noted in one patient and tongue atrophy in two patients. CONCLUSION/CONCLUSIONS:Single-fraction SRS appears to be a safe and effective upfront and adjuvant treatment option for HS. SRS may be recommended as an alternative to surgery for patients presenting with HS or as an adjuvant treatment following subtotal resection and at HS recurrence.
PMID: 35347448
ISSN: 0942-0940
CID: 5200982

Stereotactic radiosurgery for Rathke's cleft cysts: an international multicenter study

Kondziolka, Douglas; Bernstein, Kenneth; Lee, Cheng-Chia; Yang, Huai-Che; Liscak, Roman; May, Jaromir; Martínez-Álvarez, Roberto; Martínez-Moreno, Nuria; Bunevicius, Adomas; Sheehan, Jason P
OBJECTIVE:Rathke's cleft cysts (RCCs) are sellar collections from an incompletely regressed Rathke's pouch. Common symptoms of RCCs can include headaches, visual loss, and endocrinopathy. Surgery is required in some cases of symptomatic or growing RCCs. Recurrence after surgery is common (range 10%-40%). Stereotactic radiosurgery (SRS) has been used in an attempt to control growth and symptoms, but outcomes are not well known. The authors sought to study the outcomes of RCCs following Gamma Knife surgery for both salvage and initial treatment. METHODS:The outcomes of 25 patients with RCCs who underwent SRS between 2001 and 2020 were reviewed. Four patients received initial SRS and 21 were treated with salvage SRS. Diagnosis was based on imaging or histopathology. Cyst control was defined as stability or regression of the cyst. Kaplan-Meier analysis was used to determine time to recurrence and determine potential factors for recurrence. RESULTS:The respective median clinical follow-up and margin dose were 6.5 years and 12 Gy. Overall control was achieved in 19 (76%) of 25 patients, and 4 recurrences required further intervention. The average time to recurrence was 35.6 months in those RCCs that recurred. Visual recovery occurred in 14 (93.3%) of 15 patients and no new post-SRS visual deficits occurred. The presence of a pretreatment visual deficit was often an indicator of RCC regrowth. All 3 patients with pretreatment hyperprolactinemia experienced resolution after SRS. New endocrinopathy related to SRS was noted in 5 (20%) of 25 patients, all of which were thyroid and/or cortisol axis related. Upfront SRS was used in 4 patients. No new endocrinopathies or visual deficits developed after upfront SRS, and the 1 patient with a pretreatment visual deficit recovered. One of the 4 patients with upfront SRS experienced a recurrence after 7.5 years. CONCLUSIONS:SRS produced effective recovery of visual deficits and carries a low risk for new visual deficits. Cyst control was achieved in approximately three-fourths of the patients. Following SRS, patients without pretreatment visual deficits are less likely to have RCC regrowth. Endocrinopathy can occur after SRS, similar to other sellar mass lesions. Initial SRS shows the potential for long-term cyst control, with improvement of symptoms and a low risk for complications.
PMID: 35148508
ISSN: 1933-0693
CID: 5156952

Stereotactic radiosurgery for intracranial chordomas: an international multiinstitutional study

Pikis, Stylianos; Mantziaris, Georgios; Peker, Selcuk; Samanci, Yavuz; Nabeel, Ahmed M; Reda, Wael A; Tawadros, Sameh R; El-Shehaby, Amr M N; Abdelkarim, Khaled; Eldin, Reem M Emad; Sheehan, Darrah; Sheehan, Kimball; Liscak, Roman; Chytka, Tomas; Tripathi, Manjul; Madan, Renu; Speckter, Herwin; Hernández, Wenceslao; Barnett, Gene H; Hori, Yusuke S; Dabhi, Nisha; Aldakhil, Salman; Mathieu, David; Kondziolka, Douglas; Bernstein, Kenneth; Wei, Zhishuo; Niranjan, Ajay; Kersh, Charles R; Lunsford, L Dade; Sheehan, Jason P
OBJECTIVE:The object of this study was to evaluate the safety, efficacy, and long-term outcomes of stereotactic radiosurgery (SRS) in the management of intracranial chordomas. METHODS:This retrospective multicenter study involved consecutive patients managed with single-session SRS for an intracranial chordoma at 10 participating centers. Radiological and neurological outcomes were assessed after SRS, and predictive factors were evaluated via statistical methodology. RESULTS:A total of 93 patients (56 males [60.2%], mean age 44.8 years [SD 16.6]) underwent single-session SRS for intracranial chordoma. SRS was utilized as adjuvant treatment in 77 (82.8%) cases, at recurrence in 13 (14.0%) cases, and as primary treatment in 3 (3.2%) cases. The mean tumor volume was 8 cm3 (SD 7.3), and the mean prescription volume was 9.1 cm3 (SD 8.7). The mean margin and maximum radiosurgical doses utilized were 17 Gy (SD 3.6) and 34.2 Gy (SD 6.4), respectively. On multivariate analysis, treatment failure due to tumor progression (p = 0.001) was associated with an increased risk for post-SRS neurological deterioration, and a maximum dose > 29 Gy (p = 0.006) was associated with a decreased risk. A maximum dose > 29 Gy was also associated with improved local tumor control (p = 0.02), whereas the presence of neurological deficits prior to SRS (p = 0.04) and an age > 65 years at SRS (p = 0.03) were associated with worse local tumor control. The 5- and 10-year tumor progression-free survival rates were 54.7% and 34.7%, respectively. An age > 65 years at SRS (p = 0.01) was associated with decreased overall survival. The 5- and 10-year overall survival rates were 83% and 70%, respectively. CONCLUSIONS:SRS appears to be a safe and relatively effective adjuvant management option for intracranial chordomas. The best outcomes were obtained in younger patients without significant neurological deficits. Further well-designed studies are necessary to define the best timing for the use of SRS in the multidisciplinary management of intracranial chordomas.
PMID: 35120328
ISSN: 1933-0693
CID: 5153952

Stereotactic radiosurgery versus active surveillance for asymptomatic, skull-based meningiomas: an international, multicenter matched cohort study

Mantziaris, Georgios; Pikis, Stylianos; Samanci, Yavuz; Peker, Selcuk; Nabeel, Ahmed M; Reda, Wael A; Tawadros, Sameh R; El-Shehaby, Amr M N; Abdelkarim, Khaled; Emad, Reem M; Delabar, Violaine; Mathieu, David; Lee, Cheng-Chia; Yang, Huai-Che; Liscak, Roman; Hanuska, Jaromir; Alvarez, Roberto Martinez; Moreno, Nuria Martinez; Tripathi, Manjul; Speckter, Herwin; Albert, Camilo; Benveniste, Ronald J; Bowden, Greg N; Patel, Dev N; Kondziolka, Douglas; Bernstein, Kenneth; Lunsford, L Dade; Jenkinson, Michael D; Islim, Abdurrahman I; Sheehan, Jason
OBJECTIVE:The optimal management of asymptomatic, skull-based meningiomas is not well defined. The aim of this study is to compare the imaging and clinical outcomes of patients with asymptomatic, skull-based meningiomas managed either with upfront stereotactic radiosurgery (SRS) or active surveillance. METHODS:This retrospective, multicenter study involved patients with asymptomatic, skull-based meningiomas. The study end-points included local tumor control and the development of new neurological deficits attributable to the tumor. Factors associated with tumor progression and neurological morbidity were also analyzed. RESULTS:The combined unmatched cohort included 417 patients. Following propensity score matching for age, tumor volume, and follow-up 110 patients remained in each cohort. Tumor control was achieved in 98.2% and 61.8% of the SRS and active surveillance cohorts, respectively. SRS was associated with superior local tumor control (p < 0.001, HR = 0.01, 95% CI = 0.002-0.13) compared to active surveillance. Three patients (2.7%) in the SRS cohort and six (5.5%) in the active surveillance cohort exhibited neurological deterioration. One (0.9%) patient in the SRS-treated and 11 (10%) patients in the active surveillance cohort required surgical management of their meningioma during follow-up. CONCLUSIONS:SRS is associated with superior local control of asymptomatic, skull-based meningiomas as compared to active surveillance and does so with low morbidity rates. SRS should be offered as an alternative to active surveillance as the initial management of asymptomatic skull base meningiomas. Active surveillance policies do not currently specify the optimal time to intervention when meningioma growth is noted. Our results indicate that if active surveillance is the initial management of choice, SRS should be recommended when radiologic tumor progression is noted and prior to clinical progression.
PMID: 35067846
ISSN: 1573-7373
CID: 5166952

Stereotactic radiosurgery for asymptomatic petroclival region meningiomas: a focused analysis from the IMPASSE study

Mantziaris, Georgios; Pikis, Stylianos; Bunevicius, Adomas; Peker, Selcuk; Samanci, Yavuz; Nabeel, Ahmed M; Reda, Wael A; Tawadros, Sameh R; El-Shehaby, Amr M N; Abdelkarim, Khaled; Emad, Reem M; Delabar, Violaine; Mathieu, David; Lee, Cheng-Chia; Yang, Huai-Che; Liscak, Roman; Hanuska, Jaromir; Alvarez, Roberto Martinez; Moreno, Nuria Martinez; Tripathi, Manjul; Speckter, Herwin; Albert, Camilo; Bowden, Greg N; Benveniste, Ronald J; Patel, Dev N; Kondziolka, Douglas; Bernstein, Kenneth; Lunsford, L Dade; Sheehan, Jason
BACKGROUND:The optimal management of asymptomatic, petroclival meningiomas remains incompletely defined. The purpose of this study was to evaluate the safety and efficacy of upfront stereotactic radiosurgery (SRS) for patients with asymptomatic, petroclival region meningiomas. METHODS:This retrospective, international, multicenter study involved patients treated with SRS for an asymptomatic, petroclival region meningioma. Study endpoints included local tumor control rate, procedural complications, and the emergence of new neurological deficits. RESULTS:There were 72 patients (22 males, mean age 59.53 years (SD ± 11.9)) with an asymptomatic meningioma located in the petroclival region who were treated with upfront SRS. Mean margin dose and maximum dose were 13.26 (SD ± 2.72) Gy and 26.14 (SD ± 6.75) Gy respectively. Median radiological and clinical follow-up periods post-SRS were 52.5 (IQR 61.75) and 47.5 months (IQR 69.75) respectively. At last follow-up, tumor control was achieved in all patients. SRS-related complications occurred in 6 (8.33%) patients, with 3 of them (4.17%) exhibiting new neurological deficits. CONCLUSIONS:Upfront SRS for asymptomatic, petroclival region meningiomas affords excellent local tumor control and does so with a relatively low risk of SRS-related complications. SRS can be considered at diagnosis of an asymptomatic petroclival region meningioma. If active surveillance is initially chosen, SRS should be recommended when growth is noted during radiological follow-up.
PMID: 34767093
ISSN: 0942-0940
CID: 5068362

Long-term Natural History and Patterns of Sporadic Vestibular Schwannoma Growth: A Multi-institutional Volumetric Analysis of 952 Patients

Marinelli, John P; Schnurman, Zane; Killeen, Daniel E; Nassiri, Ashley M; Hunter, Jacob B; Lees, Katherine A; Lohse, Christine M; Roland, J Thomas; Golfinos, John G; Kondziolka, Douglas; Link, Michael J; Carlson, Matthew L
BACKGROUND:The current study aims to characterize the natural history of sporadic vestibular schwannoma volumetric tumor growth, including long-term growth patterns following initial detection of growth. METHODS:Volumetric tumor measurements from 3,505 serial MRI studies were analyzed from unselected consecutive patients undergoing wait-and-scan management at three tertiary referral centers between 1998 and 2018. Volumetric tumor growth was defined as a change in volume ≥20%. RESULTS:Among 952 patients undergoing observation, 622 experienced tumor growth with initial growth-free survival rates (95% CI) at 1, 3, and 5 years following diagnosis of 66% (63-69), 30% (27-34), and 20% (17-24). Among 405 patients who continued to be observed despite demonstrating initial growth, 210 experienced subsequent tumor growth with subsequent growth-free survival rates at 1, 3, and 5 years following initial growth of 77% (72-81), 37% (31-43), and 24% (18-31). Larger tumor volume at initial growth (HR 1.13, p=0.02) and increasing tumor growth rate (HR 1.31; p<0.001) were significantly associated with an increased likelihood of subsequent growth, whereas a longer duration of time between diagnosis and detection of initial growth was protective (HR 0.69; p<0.001). CONCLUSIONS:While most vestibular schwannomas exhibit an overall propensity for volumetric growth following diagnosis, prior tumor growth does not perfectly predict future growth. Tumors can subsequently grow faster, slower, or demonstrate quiescence and stability. Larger tumor size and increasing tumor growth rate portend a higher likelihood of continued growth. These findings can inform timing of intervention: whether upfront at initial diagnosis, after detection of initial growth, or only after continued growth is observed.
PMID: 34964894
ISSN: 1523-5866
CID: 5108222

Survival and outcomes in patients with ≥ 25 cumulative brain metastases treated with stereotactic radiosurgery

Benjamin, Carolina Gesteira; Gurewitz, Jason; Kavi, Ami; Bernstein, Kenneth; Silverman, Joshua; Mureb, Monica; Donahue, Bernadine; Kondziolka, Douglas
OBJECTIVE:In the era in which more patients with greater numbers of brain metastases (BMs) are being treated with stereotactic radiosurgery (SRS) alone, it is critical to understand how patient, tumor, and treatment factors affect functional status and overall survival (OS). The authors examined the survival outcomes and dosimetry to critical structures in patients treated with Gamma Knife radiosurgery (GKRS) for ≥ 25 metastases in a single session or cumulatively over the course of their disease. METHODS:A retrospective analysis was conducted at a single institution. The institution's prospective Gamma Knife (GK) SRS registry was queried to identify patients treated with GKRS for ≥ 25 cumulative BMs between June 2013 and April 2020. Ninety-five patients were identified, and their data were used for analysis. Treatment plans for dosimetric analysis were available for 89 patients. Patient, tumor, and treatment characteristics were identified, and outcomes and OS were evaluated. RESULTS:The authors identified 1132 patients with BMs in their institutional registry. Ninety-five patients were treated for ≥ 25 cumulative metastases, resulting in a total of 3596 tumors treated during 373 separate treatment sessions. The median number of SRS sessions per patient was 3 (range 1-12 SRS sessions), with nearly all patients (n = 93, 98%) having > 1 session. On univariate analysis, factors affecting OS in a statistically significant manner included histology, tumor volume, tumor number, diagnosis-specific graded prognostic assessment (DS-GPA), brain metastasis velocity (BMV), and need for subsequent whole-brain radiation therapy (WBRT). The median of the mean WB dose was 4.07 Gy (range 1.39-10.15 Gy). In the top quartile for both the highest cumulative number and highest cumulative volume of treated metastases, the median of the mean WB dose was 6.14 Gy (range 4.02-10.15 Gy). Seventy-nine patients (83%) had all treated tumors controlled at last follow-up, reflecting the high and durable control rate. Corticosteroids for tumor- or treatment-related effects were prescribed in just over one-quarter of the patients. Of the patients with radiographically proven adverse radiation effects (AREs; 15%), 4 were symptomatic. Four patients required subsequent craniotomy for hemorrhage, progression, or AREs. CONCLUSIONS:In selected patients with a large number of cumulative BMs, multiple courses of SRS are feasible and safe. Together with new systemic therapies, the study results demonstrate that the achieved survival rates compare favorably to those of larger contemporary cohorts, while avoiding WBRT in the majority of patients. Therefore, along with the findings of other series, this study supports SRS as a standard practice in selected patients with larger numbers of BMs.
PMID: 34952524
ISSN: 1933-0693
CID: 5109192

The incidence and predictors of new brain metastases in patients with non-small cell lung cancer following discontinuation of systemic therapy

London, Dennis; Patel, Dev N; Donahue, Bernadine; Navarro, Ralph E; Gurewitz, Jason; Silverman, Joshua S; Sulman, Erik; Bernstein, Kenneth; Palermo, Amy; Golfinos, John G; Sabari, Joshua K; Shum, Elaine; Velcheti, Vamsidhar; Chachoua, Abraham; Kondziolka, Douglas
OBJECTIVE:Patients with non-small cell lung cancer (NSCLC) metastatic to the brain are living longer. The risk of new brain metastases when these patients stop systemic therapy is unknown. The authors hypothesized that the risk of new brain metastases remains constant for as long as patients are off systemic therapy. METHODS:A prospectively collected registry of patients undergoing radiosurgery for brain metastases was analyzed. Of 606 patients with NSCLC, 63 met the inclusion criteria of discontinuing systemic therapy for at least 90 days and undergoing active surveillance. The risk factors for the development of new tumors were determined using Cox proportional hazards and recurrent events models. RESULTS:The median duration to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase (RTK) pathways (e.g., KRAS, EGFR) were more likely to develop new tumors (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.81, p = 2.5 × 10-3; HR 2.51, 95% CI 1.45-4.34, p = 9.8 × 10-4, respectively). CONCLUSIONS:The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or RTK pathway mutations have a higher rate of new metastases and should be followed more closely.
PMID: 34891140
ISSN: 1933-0693
CID: 5110502

Stereotactic radiosurgery for IDH wild type glioblastoma: an international, multicenter study

Bunevicius, Adomas; Pikis, Stylianos; Kondziolka, Douglas; Patel, Dev N; Bernstein, Kenneth; Sulman, Erik P; Lee, Cheng-Chia; Yang, Huai-Che; Delabar, Violaine; Mathieu, David; Cifarelli, Christopher P; Arsanious, David E; Dahshan, Basem A; Weir, Joshua S; Speckter, Herwin; Mota, Angel; Tripathi, Manjul; Kumar, Narendra; Warnick, Ronald E; Peker, Selcuk; Samanci, Yavuz; Barnett, Gene; Hefnawi, Farid El; Al Sideiri, Ghusn; Sheehan, Jason
OBJECTIVE:Isocitrate dehydrogenase (IDH) mutation status is recommended used for diagnosis and prognostication of glioblastoma patients. We studied efficacy and safety of stereotactic radiosurgery (SRS) for patients with recurrent IDH-wt glioblastoma. METHODS:Consecutive patients treated with SRS for IDH-wt glioblastoma were pooled for this retrospective observational international multi-institutional study from institutions participating in the International Radiosurgery Research Foundation. RESULTS:) for IDH-wt glioblastoma. All patients had histories of surgery and chemotherapy with temozolomide, and 98% underwent fractionated radiation therapy. MGMT status was available for 42 patients, of which half of patients had MGMT mutant glioblastomas. During median post-SRS imaging follow-up of 6 months, 52% of patients experienced tumor progression. Median post-SRS progression free survival was 4 months. SRS prescription dose of > 14 Gy predicted longer progression free survival [HR 0.357 95% (0.164-0.777) p = 0.009]. Fifty-percent of patients died during post-SRS clinical follow-up that ranged from 1 to 33 months. SRS treatment volume of > 5 cc emerged as an independent predictor of shorter post-SRS overall survival [HR 2.802 95% CI (1.219-6.444) p = 0.02]. Adverse radiation events (ARE) suggestive of radiation necrosis were diagnosed in 6/55 (10%) patients and were managed conservatively in the majority of patients. CONCLUSIONS:SRS prescription dose of > 14 Gy is associated with longer progression free survival while tumor volume of > 5 cc is associated with shorter overall survival after SRS for IDH-wt glioblastomas. AREs are rare and are typically managed conservatively.
PMID: 34797526
ISSN: 1573-7373
CID: 5049702